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Stimulation of Notch Signaling in Mouse Osteoclast Precursors
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b-Annulated 1,4-dihydropyridines as Notch inhibitors

Jorge E Gómez-Galeno1, Cecilia Hurtado2, Jiongjia Cheng1

  • 1Human BioMolecular Research Institute, 5310 Eastgate Mall, San Diego, CA 92121-2804, United States.

Bioorganic & Medicinal Chemistry Letters
|September 12, 2018
PubMed

Insights

Researchers identified a potent Notch pathway inhibitor, (+)-7, with an EC50 of 0.13 μM. This compound, derived from FLI-06, shows significantly enhanced potency for potential cancer therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • The Notch signaling pathway regulates cell proliferation and differentiation.
  • Aberrant Notch signaling is implicated in various cancers, including colorectal, pancreatic, breast cancer, and melanoma.
  • Inhibiting Notch signaling is a promising therapeutic strategy for these conditions.

Purpose of the Study:

  • To discover novel and more potent inhibitors of the Notch signaling pathway.
  • To explore structure-activity relationships of b-annulated dihydropyridine analogs.
  • To identify lead compounds for potential anti-cancer drug development.

Main Methods:

  • Screening of a library of b-annulated dihydropyridine analogs.
  • Structure-activity relationship (SAR) studies.
  • Synthesis and evaluation of individual enantiomers of promising compounds.

Main Results:

  • FLI-06 (1) was identified as an initial Notch pathway inhibitor with an EC50 ≈ 2.5 μM.
  • Racemic compound 7 demonstrated improved potency with an EC50 = 0.36 μM.
  • The (+)-7 enantiomer exhibited the highest potency with an EC50 = 0.13 μM, approximately 20-fold greater than FLI-06.

Conclusions:

  • The (+)-7 enantiomer represents a significantly more potent Notch pathway inhibitor compared to the parent compound FLI-06.
  • This finding highlights the potential of chiral optimization in developing effective Notch signaling inhibitors.
  • The identified compound warrants further investigation for its therapeutic efficacy in Notch-dependent cancers.
Keywords:
Colorectal cancerDihydropyridinesNotchNotch signaling

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